Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid

The introduction of type b Haemophilus influenzae conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufactur...

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Veröffentlicht in:Glycoconjugate journal 2011-10, Vol.28 (7), p.463-472
Hauptverfasser: Laferriere, Craig, Ravenscroft, Neil, Wilson, Seanette, Combrink, Jill, Gordon, Lizelle, Petre, Jean
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container_issue 7
container_start_page 463
container_title Glycoconjugate journal
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creator Laferriere, Craig
Ravenscroft, Neil
Wilson, Seanette
Combrink, Jill
Gordon, Lizelle
Petre, Jean
description The introduction of type b Haemophilus influenzae conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.
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subjects Algorithms
Amines - chemistry
Amines - immunology
Bacterial Capsules - immunology
Biochemistry
Biomedical and Life Sciences
Capsular polysaccharides
Design optimization
Developing Countries
Diffusion
Drug therapy
glycoconjugates
Haemophilus Infections - immunology
Haemophilus Infections - prevention & control
Haemophilus influenzae
Haemophilus influenzae type b - immunology
Haemophilus influenzae type b - pathogenicity
Haemophilus Vaccines - chemical synthesis
Haemophilus Vaccines - immunology
Humans
Hydrazines - chemistry
Hydrazines - immunology
Immunoconjugates - chemistry
Immunogenicity
Influenza
Isoelectric points
Life Sciences
Lysine
Lysine - chemistry
Lysine - immunology
Pathology
Polysaccharides - chemistry
Polysaccharides - immunology
Polysaccharides, Bacterial - chemistry
Polysaccharides, Bacterial - immunology
Precipitation
Research Design
Salts
Temperature effects
Tetanus
Tetanus Toxoid - chemistry
Tetanus Toxoid - immunology
Vaccination
Vaccines
Vaccines, Conjugate - chemistry
Vaccines, Conjugate - immunology
title Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid
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